Most of an oral glucose load is taken up by muscle in man. We have previously demonstrated the importance of carbohydrate storage in distinguishing between individuals with low and high insulin mediated glucose disposal. Reduced insulin mediated glucose storage is associated with a reduced muscle glycogen synthase activity in man. In our effort to further clarify the importance of the regulation of muscle glycogen synthase to the regulation of insulin mediated glucose storage, we have observed the following: Insulin activation of both glucose storage and glycogen synthase are not apparent below an insulin of 53 muU/ml but have similar ED50 values of 199 and 239 muU/ml. Subjects with low insulin mediated glucose disposal rates have dose response curves for both glycogen synthase and glucose storage which are shifted to the right (lower sensitivity) and have reduced capacity. Diabetic subjects have reduced fasting muscle glycogen concentrations and reduced total glycogen synthase activity. These results suggest that glycogen synthase activity is closely associated with the process of glucose storage and that alterations in the regulation of the enzyme coincide with the altered glucose storage observed in subjects with low insulin mediated glucose storage rates. The decreases in muscle G6P over the range of insulin concentrations which stimulate glycogen synthase activity suggest that this stimulation is not secondary to increased glucose transport effects on this established activator of glycogen synthase.